Betaseron is a recombinant protein that is produced by fermentation of a strain of Escherichia coli containing a plasmid for expression of human interferon beta(ser17) (in which serine is substituted for cysteine at position 17)

Analysis has been performed to determine residues where covalent modification with polyethylene glycol does not inhibit (or improves) bioactivities in vitro (in contrast, random modification decreases the bioactivity)

Betaseron (interferon beta-1b) and Rebif (interferon beta-1a), which are formulated with human serum albumin, contain more aggregated protein and particles than does Avonex (interferon beta-1a), and the high levels of aggregates correlate with higher reported rates of neutralizing-antibody formation for Betaseron and Rebif

Induces anti-drug antibodies in immune tolerant transgenic mice, such that intravenous delivery is the most immunogenic route; intramuscular, subcutaneous, and intraperitoneal delivery are similar to each other in their immunogenic effects

Decreases the expected number of contrast enhancing lesions (CELs) seen in MRI, such that new CEL formation is inhibited, but the resolution of previously-formed CELs is not enhanced, as shown by a population analysis using datasets from two different studies involving 24 individuals

Stabilizes the blood-brain barrier (BBB), based on experiments in which serum from RRMS patients treated with interferon beta-1b reduced the permeability of an in vitro BBB model (human endothelial cells co-cultured with rat astrocytes) as compared with serum from untreated patients

Downregulates expression of the integrin VLA-4/CD49d (which is implicated in MS pathology) on CD8+ T cells and on primed but not naïve CD4+ cells in MS patients, in agreement with the idea that the drug influences the interaction of immune cells and the blood-brain barrier

Inhibits MS-induced apoptosis of endothelial cells (potentially indicating a role in preserving the blood-brain barrier), as shown by experiments in which apoptosis of human umbilical endothelial cells was induced by sera from exacerbating MS patients and blocked by interferon beta-1b

Inhibits interleukin-2–induced secretion of gelatinases (matrix metalloproteinases that digest subendothelial basement membrane components) and migration across an artificial basement membrane by human T cells, suggesting that the drug might interfere with the migration of activated T cells to the central nervous system

Affects cytokine release differently in cultured CD4+ and CD8+ T cells from RRMS and PPMS patients, such that the drug inhibits interferon-gamma and induces interleukin (IL)-4 selectively in CD4+ T cells from RRMS patients; induces IL-10 in all RRMS cell populations but only slightly in PPMS cells; always inhibits IL-5; and does not affect IL-17A

Associated with increased serum levels of brain-derived neurotrophic factor, which are inversely correlated with the degree of disability (measured by the Expanded Disability Status Scale score), as shown in a study of 82 individuals with MS

Three major forms of interferon beta therapy (Avonex, Betaseron, and Rebif) are associated with a robust gene expression signature from blood that involves 25 upregulated genes; all of the drugs induce a similar maximum interferon beta activation state, although the average effect of Avonex is less than that of the other drugs

Reduces serum nitrite levels (by 71%) and the annual relapse rate (by 71%), but does not affect cytokine levels or ratios in a manner that reflects effects on disease course, based on a 3-year longitudinal study of 18 RRMS patients receiving subcutaneous interferon beta-1b as monotherapy

Affects the expression of a variety of genes, including genes with roles in antioxidant activity, mitochondrial fatty acid metabolism, and immune regulation, as shown by analysis of patient gene expression profiles; greater changes were seen in long-term versus acute dosing

Increases the expression of mRNAs encoding Toll-like receptors TLR3 and TLR7 and MyD88 (a TLR adaptor molecule) in vitro in peripheral blood mononuclear cells from healthy volunteers and in vivo in individuals with RRMS

Increases the expression Toll-like receptor 7 (TLR7) in plasmacytoid dendritic cells from healthy volunteers; subsequent stimulation of these cells with a TLR7-specific ligand then strongly increases production of interferon-alpha as compared to production in cells not pretreated with interferon beta-1b

Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start), in peripheral blood mononuclear cells from both healthy individuals and individuals with MS, as well as fetal brain cells and tumor cells; this transcript contains a unique first exon and the last 5 exons of full-length NCOA7

Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start); this induction requires activation of the interferon receptor as well as the JAK-STAT pathway

Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS as compared with the number in treatment-naïve individuals or those treated with glatiramer acetate

Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS; such cells are a significant source of interleukin-10 in these individuals and in healthy controls

Interferon beta increases blood levels of B-cell activating factor (BAFF, the primary survival factor for B cells); BAFF levels are higher in individuals with MS than in healthy controls, but those with MS who do not relapse have higher BAFF levels than those who do, as shown in a prospective longitudinal study of 170 individuals with MS over 2.3 years

Interferon beta treatment can cause the production of antibodies that bind the drug, and their prevalence varies depending on the drug preparation; in one study of 124 individuals, 38.1% of those receiving Betaferon, 21.9% receiving Rebif, and 26.8% receiving CinnoVex produced binding antibodies

Interferon beta is associated with the formation of neutralizing antibodies; in a cross-sectional study in which serum samples from 2711 individuals with MS were submitted to the same independent laboratory, such antibodies occurred at a frequency of 35% for Rebif 44 microg (subcutaneous interferon beta-1a), 22% for Betaseron (interferon beta-1b) and Rebif 22 microg, and 7.5% for Avonex (intramuscular interferon beta-1a)

Interferon beta is associated with the formation of neutralizing antibodies; in one study of 2711 individuals with MS, in those with detectable neutralizing antibodies, the titer was very high in 42% to 47% of individuals treated with interferon beta-1a but in only 22% of those treated with beta interferon-1b

Interferon beta is associated with the formation of neutralizing antibodies; a systematic review and meta-analysis of randomized and non-randomized controlled trial data indicated that interferon beta-1a (Avonex) is least likely to lead to the formation of such antibodies (2.0 to 18.9% of individuals, as compared with 16.5 to 35.4% of individuals for interferon beta-1a (Rebif) and 27.3% to 53.3% for interferon beta-1b (Betaferon/Betaseron)

Inhibits the activity of the ubiquitin/proteasome system (which is elevated in MS patients), as shown by analysis of plasma from MS patients; the level of inhibition correlates with the reduction in the number of T1-weighted enhancing lesions

During interferon beta treatment, new inflammatory events are more likely in individuals with MS who display a distinct RNA profile, with increased expression of RNAs involved in lymphocyte signaling pathways

Additively enhances the effects of 25-hydroxyvitamin D [25(OH)D] on MS activity, as shown in a study that measured serum levels of 25(OH)D and global gene expression profiles in individuals who began interferon beta-1b treatment after a CIS, who were monitored for ≤2 years

Effectiveness of interferon beta (measured in terms of a lack of relapses and disease progression), in individuals lacking neutralizing antibodies against the drug, correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study

Mean adherence rates have been determined (through the analysis of 24 studies reporting on this topic) for intramuscular interferon beta-1a, given once a week (69.4%); subcutaneous interferon beta-1b, given every other day (63.8%); subcutaneous interferon beta-1a, given 3 times a week (58.4%); and glatiramer acetate, given daily (56.8%), with better outcomes in adherent versus nonadherent individuals shown in a smaller number of studies

Associated with a relative reduction of 10.5% (Betaferon) in the risk of ≥1 relapses during 2 years of treatment and is less cost effective than natalizumab, according to a pharmacoeconomic analysis that used pre-existing data

Lack of response to interferon beta-1b treatment for 2 years is not correlated with an increase in serum levels of interleukin 17F (IL-17F), although levels of IL-17F above 200 pg/ml might forecast nonresponsiveness, based on analysis of samples from 239 RRMS patients

Because specific disease-modifying therapies (DMTs) are effective in some individuals and not others, genetic biomarkers of treatment sensitivity could be useful in DMT selection; discriminative genetic markers (variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes) have been identified, with the CCR5*d+ IFNAR1*G combination indicating interferon beta rather than glatiramer acetate treatment, based on a study of responders and nonresponders among >500 individuals treated with interferon beta or glatiramer acetate

Resumption of interferon beta treatment within two weeks after delivery (versus later in the postpartum year) does not decrease the risk of relapse in the first six months postpartum, but might decrease the risk later in the first year postpartum

Potential interferon beta treatment response genetic markers have been identified in a genome-wide association study involving 151 individuals with MS and validated in an independent group of 479 individuals

Nonresponse to interferon beta therapy is associated with an intronic variant in the gene SLC9A9, which encodes an Na+ -H+ exchanger, as shown in a genome-wide association study and validated in 3 independent cohorts

Interferon beta (used experimentally rather than interferon beta-1b) affects myeloid antigen-presenting cells, which may be responsible for immune modulation mediated by interferon beta, as shown by experiments in mice

(Recombinant mouse) interferon beta expands the population of transitional and regulatory B cells, and increases secretion of interleukin-10 in the spleen, in experimental autoimmune encephalomyelitis mice

(Recombinant mouse) interferon beta increases the production of anti-myelin oligodendrocyte glycoprotein IgG, but not IgM, in experimental autoimmune encephalomyelitis mice; disease severity does not correlate with the increased IgG levels

(Recombinant mouse) interferon beta does not provide a clinical or histopathological benefit in experimental autoimmune encephalomyelitis (EAE) mice that are deficient for B cells (muMT mice), although it does in wild-type EAE mice

Nephrotic syndrome (suggestive of lupus nephritis) has been observed in one patient (with no evidence of systemic lupus erythematosus) after long-term treatment, which partially subsided after the patient switched to glatiramer acetate

Interferon beta has been associated with thrombotic microangiopathy caused by acquired ADAMTS13 deficiency, which was in turn the result of anti-ADAMTS13 IgG antibodies that developed after interferon beta therapy in one MS patient

Association of interferon beta drugs with thrombotic microangiopathy and nephrotic syndrome has led the European Medicines Agency to require stronger label warnings for Betaferon and Extavia (August 2014)

Associated with livedo reticularis and secondary Raynaud phenomenon in one individual with MS, which, along with complications seen in other individuals, suggest that the drug can have vasoconstrictive and procoagulant effects

Exposure to Betaferon/Betaseron during pregnancy is not associated with an increased rate of birth defects or spontaneous abortion, according to data on 423 prospective pregnancies (pregnant at time of reporting) with known outcomes in a pharmacovigilance database

Exposure in would-be fathers just before (within 64 days, the duration of spermatogenesis) or at the time of conception does not appear to be associated with lower birth weight or a change in gestational age of newborns, based on an analysis of 37 cases of exposure to interferon beta

Paternal exposure was not associated with increased risk of spontaneous abortion, congenital malformations, or adverse fetal outcomes, based on a study of 39 pregnancies fathered by men with MS exposed to interferon beta at time of conception as compared with 33 pregnancies fathered by men with MS without disease-modifying therapy exposure at that time

Interferon beta was not found to be associated with an increased risk of cancer (overall or specifically breast, colorectal, lung, or prostate) over 12 years in a case-control study involving 5146 individuals with RRMS, but a non-significant trend toward an association with breast cancer was detected

; low levels of a marker of vitamin D status in the first 12 months of the study were found to be a strong risk factor for increased MS disease activity and faster progression over 5 years among individuals primarily treated with interferon beta-1b

; among participants, neither higher Epstein-Barr virus antibody levels nor higher cotinine levels (an indicator of tobacco use) correlated with a higher risk of conversion to MS, and over a 5-year followup, were not correlated with MS progression or activity

Industry-sponsored, double-blind, placebo-controlled, randomized, parallel-group, multicenter study to examine detailed MRI findings from participants in the BENEFIT trial, in which patients received interferon beta-1b (250 microg, given subcutaneously every other day) or placebo

Multicenter, double-blind, placebo-controlled, randomized trial to test the effects of interferon beta-1b (250 microg or 160 microg per m2 of body surface area, given subcutaneously every other day) on time to progression [at least 1.0 point increase on the Expanded Disability Status Scale (EDSS), or 0.5 point increase if the baseline was 6.0 or 6.5] (primary outcome) and on mean change in EDSS score, measures related to relapse, MRI activity, and results of a neuropsychological test (secondary outcomes)

Drug (at either dose) was not associated with a significant change in the time to confirmed progression of EDSS scores, but both doses were associated with benefits to relapse- and MRI-related measures

; retrospective combined analyses of the results of the European SPMS trial (1998) and the North American SPMS trial (2004) to determine reasons for the discrepancy in outcomes determined that the the European SPMS trial included patients with an earlier stage of SPMS and with more active disease, which might be relevant to the different results of the two studies

Multicenter, double-masked, randomized, placebo-controlled trial to test the effects of interferon beta-1b [8 million IU (250 microg), given subcutaneously every other day] on the time to confirmed progression of disability [1.0 point increase on the Expanded Disability Status Scale (EDSS), or a 0.5 point increase if the baseline was 6.0 or 6.5]

; retrospective combined analyses of the results of the European SPMS trial (1998) and the North American SPMS trial (2004) to determine reasons for the discrepancy in outcomes determined that the the European SPMS trial included patients with an earlier stage of SPMS and with more active disease, which might be relevant to the different results of the two studies

Multicenter, randomized, double-blind, placebo-controlled trial to test the effects of interferon beta-1b (50 microg or 250 microg, administered subcutaneously every other day) on the annual exacerbation rate and on the proportion of exacerbation-free patients (primary endpoints)

250 microg interferon beta-1b was associated with a lower annual exacerbation rate (0.84) than was 50 microg interferon beta-1b (1.17) or placebo (1.27); a larger fraction of patients in the 250 microg group (31%) were exacerbation free at 2 years as compared to those in the 50 microg group (21%) or placebo group (16%); the 250 microg dose significantly reduced the median time to first relapse; the 250 microg dose also reduced the number of new lesions per year and MRI-detected burden of disease (in a cohort of 52 patients undergoing frequent MRIs)

Double-blind extension of a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of interferon beta-1b (50 microg or 250 microg, administered subcutaneously every other day) on the exacerbation rate and the MRI burden of disease

250 microg interferon beta-1b caused a one-third reduction in the annual exacerbation rate compared to placebo in each of 5 years, but the difference was not statistically significant after the second year

Placebo-controlled pilot study to test the safety and determine the side effects of recombinant human interferon beta-1b, in which patients were treated with interferon beta-1b [0.8, 4, 8, or 16 million units (mU), given subcutaneously 3 times per week] or placebo

Dose-related trend in reduction of the exacerbation frequency was seen and the 8 mU dose was selected for further study at 24 weeks (such that 15 patients received the 8 mU dose for over 6 years); side effects decreased over time

Prospective, randomized, rater-blinded, parallel-group study to examine treatment satisfaction in individuals who had been treated with intravenous natalizumab (300 mg monthly) for at least 12 months (and had increased risk or fear of progressive multifocal leukoencephalopathy), who were then randomly assigned to either subcutaneous interferon beta-1b (250 microg every other day) or continued natalizumab treatment

Trial to compare the ability of interferon beta-1b and glatiramer acetate to suppress signs of disease activity (primary outcome, number of combined active lesions per patient per scan in first year) as measured by monthly brain MRI

Patients taking either interferon beta-1b or glatiramer acetate showed similar numbers of combined active lesions per patient for first year (primary outcome) and similar numbers of relapses for 2 years

; posthoc analysis showed that individuals who were concomitantly treated with interferon beta-1b and angiotensin receptor blockers (n=22) or angiotensin-converting enzyme inhibitors (n=49) tended to have a higher relapse rate than those treated with interferon beta-1b alone

; a higher number of relapses in year 1, as well as a higher number in the previous 2 years and ≥3 new brain lesions in year 1, are predictors of future relapses, whereas age, the presence of neutralizing antibodies, and MRI activity during year 1 are predictive of MRI activity in the future, as shown by regression analysis of 857 individuals (for clinical outcomes) and 765 individuals (for MRI outcomes) from this trial who were treated with the 250 microg interferon beta-1b dose

; among 1482 participants receiving interferon beta-1b treatment, higher levels of serum 25-hydroxyvitamin D (measured at baseline, 6 months, and 12 months) were associated with a lower cumulative number of new active lesions observed between baseline and the last MRI, but serum 25-hydroxyvitamin D levels were not significantly associated with clinical disease progression or brain atrophy

In the interferon beta-1b group, 43.3% of the patients remained relapse-free, as compared to 56.7% in the interferon beta-1a (subcutaneous) and 20% in the interferon beta-1a (intramuscular) groups; the Expanded Disability Status Scale score decreased in the interferon beta-1b and interferon beta-1a (subcutaneous) groups, but remained stable in the interferon beta-1a (intramuscular) group

Multicenter, controlled, open-label, randomized, head-to-head trial to compare the effects of interferon beta-1a (22 microg administered subcutaneously once a week) versus interferon beta-1b (250 microg administered subcutaneously every other day) on the annualized relapse rate and the time to first relapse (primary endpoints) and the time to sustained progression (secondary endpoint)

The interferon beta-1b regime was more effective than the interferon beta-1a regime; the proportion of patients who remained relapse free over 2 years was 51% for interferon beta-1b versus 36% for interferon beta-1a and the proportion of patients who remained free from new T2 lesions was 55% for interferon beta-1b versus 26% for interferon beta-1a

Meta-analysis of all published observational studies (14) that examined the long-term effect of glatiramer acetate or interferon beta; the primary outcome was the effect on disease progression to secondary phase (SP) or to a sustained Extended Disability Status Scale (EDSS) score of 6

All except two of the studies examined described a consistent effect on long-term disease progression and nonparametric tests showed a pooled effect on EDSS score progression or progression to SP that was significant, indicating that the drugs appear to reduce the long-term risk of disability progression

Industry-funded study using a Markov model to estimate the cost-effectiveness of dimethyl fumarate versus interferon beta-1a (44 microg or 30 microg), interferon beta-1b (250 microg), teriflunomide, glatiramer acetate, and fingolimod from a French societal perspective; event probabilities were taken from pivotal dimethyl fumarate clinical trials and the London Ontario Dataset

Dimethyl fumarate and interferon beta-1a (44 microg) were found to be the best options, dominating the other therapies with respect to quality-adjusted life years and cost; from a societal perspective, the incremental cost-effectiveness ratio of dimethyl fumarate versus interferon beta-1a (44 microg) was €13,110 per quality-adjusted life year

Brain volume measurements appear to be affected by inflammatory activity, such that a higher number of gadolinium-enhancing lesions at baseline was associated with greater reductions in brain volume and white matter volume (but not grey matter volume) over the first year of treatment

Study to compare the risk of early relapse and disease progression in individuals with stable disease on injectable therapy (glatiramer acetate, interferon beta-1a, or interferon beta-1b) who switch to oral therapy (dimethyl fumarate, fingolimod, or teriflunomide) versus individuals who remain on injectable therapy, using data from the MSBase Registry, an international, longitudinal, observational registry that prospectively collects MS-related information

Observational study to examine the relationship between vitamin D status, measured as serum 25-hydroxyvitamin D (25[OH]D) concentration adjusted for season, and disease activity (time to relapse or the development of a new gadolinium-enhancing lesion) in individuals treated with interferon beta-1a, interferon beta-1b, glatiramer acetate, or fingolimod

Alemtuzumab was found to be the most protective against relapses during the first 24 months of therapy (moderate quality evidence); the next most protective were found to be mitoxantrone (very low quality evidence), natalizumab (high quality evidence), and fingolimod (moderate quality evidence); mitoxantrone (low quality evidence) was found to be the most effective at delaying disability worsening, followed by alemtuzumab (low quality evidence) and natalizumab (moderate quality evidence); these results must be interpreted conservatively because few trials have been performed for most of the drugs

The Expanded Disability Status Scale (EDSS) score at baseline and the change in this score during the randomized controlled trial were the best means of predicting the EDSS score after 10 years; interferon beta-1b treatment during the controlled trial was not convincingly associated with a favorable long-term outcome

Observational, multicenter, prospectively acquired cohort study to examine the effects of fingolimod versus interferon beta or glatiramer acetate in individuals (in the Italian iMedWeb registry) who had discontinued natalizumab; the risk of relapse was first estimated during the washout and new therapy periods using Poisson regression analyses in separated models; individuals who switched to fingolimod or interferon beta/glatiramer acetate were also propensity score-matched before further modeling

The risk of relapse after switching drugs was greater in those with a washout period >3 months, with more relapses before and during natalizumab therapy, and with comorbidities; the risk of an initial relapse after switching treatments was lower in individuals treated with fingolimod versus interferon beta/glatiramer acetate, although the time to 3-month confirmed disability was similar between groups

Retrospective cohort study to examine adherence to intramuscular and subcutaneous interferon beta-1a (Avonex and Rebif), interferon beta-1b (Betaferon), and glatiramer acetate (Copaxone) among insured individuals, using pharmacy claims data from the German Institute for Drug Use Evaluation from 2001 through 2009; the medication possession ratio served as a measure of compliance

Overall compliance was 39.9%, with small differences between the drugs [Avonex (42.8%), Betaferon (40.6%), Rebif (39.2%), Copaxone (37%)]; overall persistence, after 24 months, was 32.3% (such that in 32.3% of the therapy cycles discontinuations or interruptions did not occur)

Comparison of relapse rates and time to relapse, using US administrative claims data from the Truven Health MarketScan Research Databases and propensity score matching, in individuals treated with platform therapy (interferon beta or glatiramer acetate) or natalizumab

Natalizumab was associated with a reduced rate of relapse (which occurred in 26.5% of individuals in the natalizumab group and 35.5% in the platform group) and greater time to relapse (308 days for the natalizumab group and 283 days for the platform group)

Analysis to estimate the cost-effectiveness of early versus delayed treatment with interferon beta-1b in Spain, using data from the BENEFIT trial (in which individuals with CIS received interferon beta-1b or placebo for 2 years, followed by interferon beta-1b for all participants)

Early versus delayed interferon beta-1b treatment after CIS was found to be more effective and less costly based on a social perspective, but not necessarily based on the perspective of the Spanish Health System, for which non health-related costs are not a factor

Analysis of data from the MSBase registry and the TYSABRI Observational Program to compare the effects of switching to natalizumab versus switching between interferon beta and glatiramer acetate in individuals who experienced a relapse while on interferon beta or glatiramer acetate; datasets were propensity matched

Switching to natalizumab was associated with a reduction in annualized relapse rate in the first year by 65 to 75% and a reduction in the risk of confirmed disability progression over the first 24 months by 26% as compared with switching between interferon beta and glatiramer acetate

High persistence with injectable DMTs was observed; the median time-to-discontinuation was 11.1 years for all injectable DMTs and 8.6 years for the first DMT (with individuals originally prescribed glatiramer acetate staying on treatment longer)

Analysis of data from the MSBase registry to compare the effects of switching to fingolimod versus an injectable therapy (interferon beta or glatiramer acetate) on the annualized relapse rate (ARR), disability progression, and therapy persistence in individuals who were originally treated with an injectable disease-modifying therapy and who had had on-treatment disease activity ≤12 months before the switch; the new treatment was given for ≥3 months after the switch

Observational, prospective, cohort study to examine the connection between adherence to MS disease-modifying therapies (DMTs, which included interferon beta and glatiramer acetate) and the risk of relapse; participants were recruited by specific pharmacies and the medication possession ratio (MPR, derived from pharmacy shipment records) was used as a measure of adherence; electronic data capture was also used and involved monthly entries by participants

Higher DMT adherence was associated with better clinical results, such that the odds of relapse for an individual in a higher adherence group (MPR >0.9) were 64% that of an individual in a lower adherence group (MPR <0.5)

Pairwise analysis of data from the international MSBase registry to compare the real-world effectiveness of glatiramer acetate, subcutaneous interferon beta-1a, intramuscular interferon beta-1a, and interferon beta-1b, as measured by relapse and disability outcomes

Glatiramer acetate and subcutaneous interferon beta-1a were associated with a slightly lower incidence of relapses as compared with intramuscular interferon beta-1a and interferon beta-1b, but the 12-month confirmed progression of disability did not differ between drugs

Both types of drugs were similarly effective clinically at 24 months, but 1 study indicated that relapse rates were lower in the glatiramer acetate group at 36 months; the increase in MRI lesion burden was lower in the interferon beta versus glatiramer acetate groups

Company-sponsored, retrospective study to compare persistence with and adherence to fingolimod versus glatiramer acetate, interferon, and natalizumab using administrative claims data from the US PharMetrics Plus database

Drug discontinuation rates were lower for fingolimod (27.9%) versus other therapies [glatiramer acetate (39.5%), interferons (43.7%), natalizumab (39.5%)]; fingolimod was also associated with a lower risk of non-adherence compared to the other therapies

Prospective, observational study that monitored women exposed to interferon beta-1b during pregnancy to determine rates of negative outcomes; women were enrolled in an observational registry between 2006 and 2011

Three-arm, randomized, parallel study to compare the effects of different interferon beta preparations [Avonex and Rebif (interferon beta-1a) and Betaferon (interferon beta-1b)] on cognitive function, which was assessed at baseline and after 12 months of treatment using the Brief Repeatable Battery of Neuropsychological Tests

After switching from interferon beta (on which 33.3% of individuals in each cohort experienced at least one relapse), a lower proportion of patients in the fingolimod cohort had at least one relapse (12.9% versus 25.0% for the glatiramer acetate cohort); the annual relapse rate was 0.19 for the fingolimod cohort and 0.51 for the glatiramer acetate cohort

Health-department- and industry-funded, prospective, observational study to examine the effects of long-term therapy with interferon beta or glatiramer acetate on disability and quality of life, in which data from a cohort of individuals being treated with these drugs in clinical practice in the UK were compared with data from a matched, untreated cohort in British Columbia (for which data had been collected before the introduction of these drugs); furthermore, modeling approaches were used to calculate the expected progression of disease with and without treatment; the aim is to examine whether treatment is cost-effective (i.e., if worsening quality of life, which is related to disability progression, is reduced to a particular target set by the UK government) over the long-term

Over a 6-year followup period, with data modelled over a trajectory of 20 years, individuals in the UK cohort taking glatiramer acetate or interferon beta fared better (exhibited 24 to 40% less disability progression) than those in the untreated cohort, indicating that the shorter-term effects on disability observed in clinical trials are maintained; furthermore, the drugs were found to be cost-effective based on specific criteria in the UK

Observational study to examine whether a reduction in the recommended frequency of administration of subcutaneous interferon beta-1a or -1b, or a change to once-weekly intramuscular interferon beta-1a, affects clinical and MRI outcomes in individuals who had been treated with the recommended frequency of subcutaneous interferon beta for 24 months

Reducing the frequency of subcutaneous interferon beta was associated with increased relapse risk and MRI activity, whereas changing to intramuscular interferon beta-1a was associated with increased relapse risk but not MRI activity; younger age was a risk factor for the restart of disease activity after the reduction in administration frequency

Relative to the other therapies, intramuscular interferon beta-1a and glatiramer acetate were associated with fewer discontinuations because of safety concerns (however, glatiramer acetate was associated with lower patient-reported efficacy and higher burden) and subcutaneous interferon beta-1a was associated with more difficulties in tolerability; among individuals who remained on therapy, intramuscular interferon beta-1a was associated with less self-reported disability progression

Study to evaluate the net risks and benefits of natalizumab versus fingolimod, interferon beta, or no treatment over sub-groups with different progressive multifocal leukoencephalopathy (PML) risk; a Markov cohort model was designed to examine the effects of treatment on quality-adjusted life years

Retrospective study to examine whether interferon beta-1a or -1b is associated with a higher level of depression than glatiramer acetate; participants completed a depression inventory when treatment began and every 6 months afterwards

Industry-sponsored, prospective, observational, noninterventional, multinational, real-world study to examine ease of use of the ExtaviJect® 30G device, an autoinjector for self-administration of subcutaneous interferon beta-1b (Extavia), as well as compliance with treatment while using this device

Industry-sponsored, non-interventional extension study to examine the long-term effects of early treatment with interferon beta-1b in individuals who had experienced a first neurological event suggestive of MS; patients enrolled in the original trial received either interferon beta-1b (250 microg every other day) or placebo, whereas all patients had the option of receiving interferon beta-1b in an extension for up to 5 years (patients and study personnel remained unaware of the initial treatment group)

; assessments 3, 5, and 8 years after randomization showed that early treatment was associated with advantages for most clinical and MRI parameters, but the median Expanded Disability Status Scale score was the same for early treatment and delayed treatment groups

; at 11 years, 278 of the original 468 individuals were enrolled; the early treatment group continued to show benefits versus the delayed treatment group; benefits included a reduced risk for MS (65.2% versus 75%), a reduced risk for SPMS (4.5% versus 8.3%), more time to the first relapse, and a reduced annualized relapse rate

Industry-sponsored, prospectively planned, open-label follow-up study to compare the effects of early versus delayed interferon beta-1b treatment on the time to clinically definite MS and on other measures such as disability progression; patients enrolled in the original trial received either interferon beta-1b (250 microg every other day) or placebo, whereas all patients had the option of receiving interferon beta-1b in the extension (patients and study personnel remained unaware of the initial treatment group)

Early treatment with interferon beta-1b reduced the risk of conversion to clinically definite MS by 37% as compared to delayed treatment with interferon beta-1b, but early treatment did not change long-term disability outcomes; early treatment was, however, associated with more improvement in cognition

; further analysis of 435 patients showed that, during both phases of the trial, the number of persisting T1 hypointensities (also known as persistent black holes) per patient was lower in the early versus delayed treatment arm

Systematic review of published randomized, controlled clinical trials to compare the effects of dimethyl fumarate to those of existing disease-modifying treatments; relative effect sizes were derived from mixed treatment comparisons

Dimethyl fumarate (240 mg twice a day) was associated with a greater reduction in the annualized relapse rate (ARR) than placebo, interferon beta-1a, interferon beta-1b, glatiramer acetate, and teriflunomide (7 mg and 14 mg doses); dimethyl fumarate and fingolimod showed similar effects on the ARR; natalizumab was associated with a greater reduction in the ARR than dimethyl fumarate; dimethyl fumarate was associated with favorable safety outcomes; variability in how outcomes were defined and in the heterogeneity of enrolled individuals in the included trials were limitations of this review

Most individuals (92.8%) began treatment with either interferon beta or glatiramer acetate, but individuals who began treatment with natalizumab were more likely to continue with that treatment (32.3% versus 16.9%) and were less likely to have a treatment gap or switch treatments

DMTs were associated with increased cardiovascular risk factors, such as increased diastolic blood pressure; as compared with a lack of DMT, interferon beta-1b and glatiramer acetate were associated with higher risk and natalizumab with lower risk; additionally, cardiovascular drugs in DMT-naïve individuals were associated with increased MS severity

Retrospective study to examine the potential long-term effects of disease modifying drugs (DMDs, primarily interferon beta or glatiramer acetate) during pregnancy on the resulting offspring, using medical data from the children (aged 1 to 39 years at the time of the study) of women with MS who (i) were not exposed to disease-modifying therapies 3 months before pregnancy or during pregnancy or (ii) had 2 or more weeks exposure to DMDs during this period

Company-sponsored, retrospective study to assess real-world differences in relapse rates in individuals with MS who began fingolimod, interferon beta, or glatiramer acetate treatment between 1 Oct 2010 and 31 Mar 2011 (and who had experienced a relapse in the previous year); relapses were identified using a claims-based algorithm and administrative claims data from the US PharMetrics Plus database (rather than clinical assessment)

Prospective national multicenter cohort study to examine how the use of electronic versus paper diaries to document self-administered injections of interferon beta-1b might affect adherence to that treatment

Fingolimod was associated with a better response for 2 outcomes (patients free of relapse, patients without MRI progression) as compared with interferon beta-1a (Avonex); interferon beta-1b (Betaferon) was associated with a better response for 2 outcomes (patients without disease progression, patients without MRI progression) as compared with interferon beta-1a (Avonex); and natalizumab might be more effective than other treatments for 2 outcomes (patients free of relapse, patients without MRI progression); conclusions about patients with adverse events could not be reached because of a lack of data

Randomized, prospective, parallel-group, rater-blinded pilot study to compare disease activity in individuals who switched from natalizumab to interferon beta-1b to activity in those who remained on natalizumab; participants in the study had been free of disease activity on natalizumab for at least 6 months

78% of those who switched to interferon beta-1b remained free of relapses and 25% did not display new T2 lesions; the group who remained on natalizumab had more favorable outcomes (either statistically significant or showing a trend) for a number of endpoints, such as number of relapses, proportion of patients without a relapse, and the number of new T2 lesions at month 6, but the time to the first relapse was not significantly different between the two treatment groups

Study to evaluate the relationship between peripheral blood levels of Th17 cells and the efficacy of interferon beta-1b (250 microg dose), as measured by changes in the Expanded Disability Status Scale score and T2 lesion number between baseline and the end of the study period

Interferon beta-1b was considered effective for some but not all patients; those for whom treatment was ineffective also displayed an increase in Th17 cells before treatment, suggesting that RRMS mediated by Th17 cells is not responsive to this drug

Natalizumab and interferon beta-1a (Rebif) were determined to be better than other treatments for preventing relapses in RRMS over the short term (24 months), and these two drugs probably inhibited disability progression in RRMS in this time period, although they are linked with long-term adverse events; in RRMS, interferon beta-1b and mitoxantrone probably decreased the probability of relapses, whereas interferon beta-1a (Avonex) and cyclophosphamide lacked convincing efficacy data; none of the treatments effectively decreased disability progression in progressive MS

Longitudinal study to monitor the effects of long-term interferon beta-1b on cognition; patients originally participated in a pivotal interferon beta-1b trial published in 1993/1995, with 9 receiving interferon beta-1b and 7 receiving placebo; after 5 years, all received interferon beta-1b

Over 16 years, cognitive function was relatively stable, indicating that the drug has positive effects on cognition; visual memory performance was better in the placebo/interferon beta-1b group, whereas verbal memory was better in the interferon beta-1b treatment group

Multicenter Australian cohort study using the MSBase platform to characterize use of disease-modifying therapies (DMTs, which included interferon beta, glatiramer acetate, and natalizumab); specifically, treatment persistence, factors that predict treatment discontinuation, and rates of switching between DMTs were studied

Treatment persistence in this study was short, such that patients remained on their first DMT for 2.5 years (median) and on their next DMT for 2.3 years; annualized switch or cessation rates were 9.5 to 12.5% (interferon beta), 11.6% (glatiramer acetate), and 4.4% (natalizumab); younger age and higher disability scores predicted DMT discontinuation

Data from two MS patient registries [TYSABRI Observational Program (TOP) and MSCOMET] were used in a propensity-matched analysis to compare the effects of natalizumab, interferon beta, and glatiramer acetate on relapses

Natalizumab was associated with a lower rate of first relapse as compared to interferon beta and glatiramer acetate; relapses in patients treated with natalizumab also occurred more slowly than in those treated with the other drugs

Observational study to determine clinical- and MRI-based predictors of response to glatiramer acetate and interferon beta; patients were considered "responders" if clinical and MRI activity were absent during treatment and "non-responders" in the presence of MRI activity or if the reduction in annualized relapse rate (ARR) was <50% of the ARR in the 2 previous years

Analysis to assess the effect of real-world adherence (estimated from a study of a single claims database of a national pharmacy benefit manager) on the cost-effectiveness (the cost per avoided relapse) of fingolimod, subcutaneous interferon beta-1b (Extavia or Betaseron) and interferon beta-1a, glatiramer acetate, and intramuscular interferon beta-1a

Industry-sponsored, randomized, parallel-group, multicenter, open-label study to examine the tolerability, effects at injection site, and efficacy of a serum-free version of interferon beta-1a (produced without fetal bovine serum and lacking the excipient human serum albumin) versus interferon beta-1b; patients received either interferon beta-1a titrated to 44 microg subcutaneously three times weekly or interferon beta-1b titrated to 250 microg subcutaneously every other day over 12 weeks, followed by interferon beta-1a (44 microg three times weekly) for all patients for 82 to 112 weeks; the mean change in patient-reported pain at the injection site over the first 21 injections at full dose was the primary endpoint

Part of a larger, open-label, multicenter, prospective, observational Phase IV clinical study (titled Success of Titration, analgesics, and BETA nurse support on Acceptance Rates to early MS Treatment with Betaseron®, or START); this particular analysis looked for correlations between the response to interferon beta-1b and immune markers

Randomized, open-label, multicenter, two-arm pilot study to evaluate the safety and tolerability of a combination of the immunosuppressant tacrolimus [orally two times per day at a dose to reach either low (1-5 ng/ml) or high (5-10 ng/ml) blood levels] with interferon beta-1b therapy (250 microg given subcutaneously every other day); the idea is to target more than one autoimmune process by using two drugs

Systematic review of the literature for information about the effects of interferon beta, glatiramer acetate, or natalizumab on the offspring of MS patients who used these disease-modifying drugs (DMDs) during pregnancy

Retrospective cohort study, based on prospectively collected data, to compare the effects of interferon beta (-1a or -1b) versus placebo on the progression to disability, such that the main outcome measure was time from eligibility for treatment with interferon beta to a confirmed sustained score of 6 on the Expanded Disability Status Scale (EDSS)

Interferon beta was not associated with a reduction in the progression of disability, such that 10.8% of patients in the treated group, 5.3% in the contemporary untreated group, and 23.1% in the historical untreated group reached an EDSS score of 6

Meta-analysis of placebo-controlled and head-to-head trials, which evaluated the effects of one or more drugs (fingolimod, interferon beta-1a, interferon beta-1b, and/or glatiramer acetate), to compare the effects of fingolimod versus the other treatments on the annualized relapse rate (ARR)

Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis

Open-label study to evaluate the effectiveness and tolerability of interferon beta in patients younger than 16 years; patients were treated with either interferon beta-1a (30 microg, intramuscularly once a week) or interferon beta-1b (250 microg, subcutaneously every other day)

Randomized, long-term cohort study to compare all-cause mortality over 21 years between patients who received either 250 microg interferon beta-1b (administered subcutaneously every other day for up to 5 years) or placebo in a pivotal interferon beta-1b trial published in 1993/1995

Patients who were originally randomly assigned to 250 microg interferon beta-1b had a significant reduction in all-cause mortality over 21 years as compared with those receiving placebo, such that the hazard rate of death was reduced 46.8% among the treated patients

; additional analyses showed that the excessive deaths among patients who received placebo during the original randomized controlled trial were primarily related to MS, particularly MS-related pulmonary infections (81 deaths had been recorded among the 366 patients; the cause of death and/or its relationship to MS were determined for 71/81 of the deaths)

Observational, multicenter study to evaluate changes in spasticity after a switch from interferon beta to glatiramer acetate treatment, with the primary endpoint made up of changes in the Penn Spasm Frequency Scale, Modified Ashworth Scale, Adductor Tone Rating Scale, and Global Pain Score at 3 and 6 months after the switch

; an analysis from the Spanish National Health System perspective showed that costs during interferon beta treatment were 1.5 times higher than those during glatiramer acetate treatment; switching to glatiramer acetate was associated with reduced costs of therapy and management of relapses, as well as reduced need for spasticity treatment

Industry-sponsored, cross-sectional, observational, cohort study to evaluate the long-term benefit of interferon beta-1b therapy in patients who participated in a pivotal interferon beta-1b trial published in 1993/1995 (involving 50 microg or 250 microg interferon beta-1b, administered subcutaneously every other day for up to 5 years), such that treatment and disease status after 16 years was assessed, but interferon beta-1b was not administered as part of this study

Physical and cognitive outcomes after 16 years correlated with baseline disability; physical outcome but not cognition correlated with disability accrual and annualized relapse rates during the randomised controlled trial, whereas cognitive but not physical outcomes correlated with baseline measures of lesion burden and atrophy as measured by MRI; given that better correlations were seen for several baseline measures, long term outcomes might be determined mostly early during the course of the disease

Results from five randomized, placebo-controlled trials (RTCs) were selected for further analysis after assessment of all RTCs that evaluated the efficacy of interferon beta-1a and -1b in SPMS; the goal was to determine whether interferon beta can safely reverse or slow SPMS